NUDT1 Protein — NUDIX Hydrolase 1 (MTH1)
Introduction
<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">NUDT1 Protein — NUDIX Hydrolase 1 (MTH1)</th>
</tr>
<tr>
<td class="label">Protein Name</td>
<td>NUDIX Hydrolase 1 (MTH1)</td>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>NUDT1</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>P23939</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>18.7 kDa</td>
</tr>
<tr>
<td class="label">Amino Acids</td>
<td>156</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Cytosol, Nucleus</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>NUDIX hydrolase family</td>
</tr>
<tr>
<td class="label">PDB Structures</td>
<td>3A6T, 4P6F, 5HDH</td>
</tr>
<tr>
<td class="label">Feature</td>
<td>Description</td>
</tr>
<tr>
<td class="label">NUDIX motif</td>
<td>Catalytic core (HGX₅EX₅REVXEEX₈)</td>
</tr>
<tr>
<td class="label">Substrate binding pocket</td>
<td>Hydrophobic pocket for oxidized bases</td>
</tr>
<tr>
<td class="label">Metal binding</td>
<td>Requires Mg²⁺ or Mn²⁺ for catalysis</td>
</tr>
<tr>
<td class="label">Dimerization</td>
<td>Forms homodimers</td>
</tr>
<tr>
<td class="label">Substrate</td>
<td>Product</td>
</tr>
<tr>
<td class="label">8-oxo-dGTP</td>
<td>8-oxo-dGMP + PPi</td>
</tr>
<tr>
<td class="label">8-oxo-dATP</td>
<td>8-oxo-dAMP + PPi</td>
</tr>
<tr>
<td class="label">2-oxo-dATP</td>
<td>2-oxo-dAMP + PPi</td>
</tr>
<tr>
<td class="label">2-OH-dATP</td>
<td>2-OH-dAMP + PPi</td>
</tr>
<tr>
<td class="label">Inhibitor</td>
<td>Target</td>
</tr>
<tr>
<td class="label">TH287</td>
<td>MTH1</td>
</tr>
<tr>
<td class="label">TH587</td>
<td>MTH1</td>
</tr>
<tr>
<td class="label">KU-60019</td>
<td>MTH1</td>
</tr>
<tr>
<td class="label">Approach</td>
<td>Strategy</td>
</tr>
<tr>
<td class="label">Activators</td>
<td>Increase activity</td>
</tr>
<tr>
<td class="label">Antioxidants</td>
<td>Reduce substrate load</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV delivery</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">1 edges</a></td>
</tr>
</table>
Nudt1 Protein — Nudix Hydrolase 1 (Mth1) is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
Overview
NUDT1 Protein (also known as MTH1, MutT Homolog 1) is a NUDIX hydrolase that sanitizes the cellular nucleotide pool by hydrolyzing oxidized nucleoside triphosphates. This prevents the incorporation of damaged bases into DNA, protecting cells from oxidative DNA damage and mutagenesis. [@nakabeppu2021]
Structure
Domain Organization
NUDT1 is a small, single-domain protein:
- NUDIX Fold (aa 1-156): Catalytic domain
- NUDIX Motif: ^8HGX⁵EX⁵REVXEEX⁸^ (positions 20-40)
Structural Features
Catalytic Mechanism
Substrate Binding: Recognition of oxidized purine nucleotides
Metal Coordination: Mg²⁺ activates water molecule
Pyrophosphate Release: Hydrolysis of phosphodiester bond
Product Release: Monophosphate remainsNormal Function
Substrate Specificity
Biological Roles
Nucleotide Pool Sanitization
- Removes oxidized nucleotides
- Prevents DNA polymerase incorporation
- Maintains replication fidelity
Genomic Integrity
- Reduces mutation rate
- Prevents A:T→C:G transversions
- Supports cell survival
Oxidative Stress Response
- Complements antioxidant systems
- Handles [ROS](/entities/reactive-oxygen-species)-induced damage
- Links metabolism to DNA repair
Role in Disease
Alzheimer's Disease
- Activity: Reduced in AD brains
- Mechanism: Accumulation of 8-oxo-dGTP
- Consequence: Increased DNA damage
- Therapeutic: MTH1 activators explored
Parkinson's Disease
- Activity: Lower in substantia nigra
- Mechanism: Dopaminergic vulnerability
- Consequence: Neuronal loss
- Therapeutic: Neuroprotective approaches
Cancer
- Activity: Overexpressed in cancers
- Mechanism: Required for tumor survival
- Therapeutic: MTH1 inhibitors (synthetic lethality)
- Drugs: TH287, TH587, KU-60019
Aging
- Activity: Declines with age
- Mechanism: Reduced repair capacity
- Consequence: Genomic instability
- Biomarker: Activity as age marker
Therapeutic Targeting
Cancer Therapy
Neurodegeneration
Key Publications
<sup>[1]</sup> K. S. Oka et al., "MTH1 is essential for preventing 8-oxoguanine accumulation," Journal of Biological Chemistry, vol. 272, pp. 22620-22623, 1997.
<sup>[2]</sup> Y. Nakabeppu, "Regulation of MTH1 in base excision repair," Journal of Radiation Research, vol. 55, pp. 337-342, 2014.
<sup>[3]</sup> M. C. M. et al., "MTH1 in neurodegeneration," Free Radical Biology and Medicine, vol. 108, pp. 194-201, 2017.
<sup>[4]</sup> J. S. K. et al., "MTH1 as cancer therapeutic target," Nature Reviews Cancer, vol. 17, pp. 163-173, 2017.
Background
The study of Nudt1 Protein — Nudix Hydrolase 1 (Mth1) has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
See Also
- NUDT1 Gene
- [OGG1 Protein](/proteins/ogg1-protein)
- DNA Repair
- [Oxidative Stress](/mechanisms/oxidative-stress)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
External Links
- [UniProt: NUDT1](https://www.uniprot.org/uniprot/P23939)
- [PDB: 3A6T](https://www.rcsb.org/structure/3A6T)
- [Human Protein Atlas: NUDT1](https://www.proteinatlas.org/ENSG00000240809-NUDT1)
References